Benzonaphthyridine

ABSTRACT

Compounds 8,9-diethoxy-2-methyl-6-[4(p-toluenesulfonamide) phenyl]-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine and 9-ethoxy-8-methoxy-2-methyl-6-[4-(p-toluenesulfonamido)phenyl]-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine and medicament compositions based thereon are useful for treating airway disorders, high blood pressure disorders and concomitant disorders connected therewith.

RELATED DISCLOSURE

The subject invention is directed to compounds related to thosedisclosed and claimed in application Ser. No. 09/284,458 (now U.S. Pat.No. 6,008,215), filed Apr. 16, 1999.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel benzonaphthyridines, a process for theirpreparation, their use and medicaments containing them. The compoundsaccording to the invention are used in the pharmaceutical industry forthe preparation of medicaments.

KNOWN TECHNICAL BACKGROUND

WO91/17991 describes under the title “New sulphonyl compounds” certainbenzonaphthyridine derivatives, which are to be suitable for thetreatment of airway disorders. In WO93/09780 and in DE-OS 4310050 theuse of these benzonaphthyridine derivatives for the treatment ofdermatoses, allergic rhinitis and conjunctivitis as well as of nasalpolyps is described. For the compound(−)-cis-8,9-Dimethoxy-2-methyl-6-[4-(p-toluenesulfonamido)-phenyl]-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine,which is particularly emphasized in WO91/17991, WO93/09780 and DE4310050, the WHO has proposed the INN Tolafentrine.

DESCRIPTION OF THE INVENTION

The invention relates to compounds of the formula I

in which

R1 is ethoxy,

R2 is methoxy or ethoxy,

and the salts of these compounds.

The compounds of the formula I are chiral compounds having chiralcenters in positions 4a and 10b. The Invention therefore both comprisesall conceivable pure diastereomers and pure enantiomers, and theirmixtures in any mixing ratio, including the racemates. Preferredcompounds of the formula I are those in which the hydrogen atoms in thepositions 4a and 10b are cis to one another.

Particularly preferred are the compounds

(−)-cis-8,9-Diethoxy-2-methyl-6-[4-(p-toluenesulfonamido)-phenyl]-1,2,3,4,4a,10b-hexahydro-benzo-[c][1,6]naphthyridineand

(−)-cis-9-Ethoxy-8-methoxy-2-methyl-6-[4-(p-toluenesulfonamido)-phenyl]-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine

and the salts of these compounds.

Suitable salts for compounds of the formula I preferably are all acidaddition salts. Particular mention may be made of the pharmacologicallytolerable salts with the inorganic and organic acids customarily used inpharmacy. Examples of such suitable salts are water-soluble andwater-insoluble acid addition salts with acids such as for example,hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid,sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonicacid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where theacids are employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

Pharmacologically intolerable salts, which can be obtained, for example,as process products during the preparation of the compounds according tothe invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

According to expert's knowledge the compounds of the invention as wellas their salts may contain, e.g. when isolated in crystalline form,varying amounts of solvents. Included within the scope of the inventionare therefore all solvates and in particular all hydrates of thecompounds of formula I as well as all solvates and in particular allhydrates of the salts of the compounds of formula I.

The invention further relates to a process for the preparation of thecompounds of the formula I, in which R1 and R2 have the meaningsindicated above, and their salts.

The process is characterized in that

a) compounds of the formula II

 in which R1 and R2 have the abovementioned meanings, are reacted with areactive derivative of p-toluenesulfonic acid, or in that

b) compounds of the formula III

 in which R1 and R2 have the abovementioned meanings, are subjected to acyclocondensation reaction

and in that, If desired, compounds of the formula I obtained accordingto a) or b) are then converted Into their salts, or in that, if desired,salts of the compounds of the formula I obtained according to a) or b)are then converted into the free compounds.

The reaction of compounds of the formula II with reactive derivatives ofthe p-toluenesulfonic acid (for example, a p-toluenesulfonic acidhalide, particularly the acid chloride) is carried out in inert solventsin a manner known to the expert for the preparation of sulfonamides. Thereaction is preferably carried out in the presence of an auxiliary base,such as for example, triethylamine or pyridine.

The cyclocondensation is carried out in a manner known per se to theperson skilled in the art according to Bischler-Napieralski (e.g. asdescribed in J. Chem. Soc., 1956, 4280-4282) in the presence of asuitable condensing agent, such as, for example, polyphosphoric acid,phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide,thionyl chloride or preferably phosphorus oxychloride, in a suitableinert solvent, e.g. in a chlorinated hydrocarbon such as chloroform, orin a cyclic hydrocarbon such as toluene or xylene, or another inertsolvent such as acetonitrile, or without a further solvent using anexcess of condensing agent, preferably at elevated temperature, inparticular at the boiling temperature of the solvent or condensing agentused.

The described methods of preparation can be carried out analogously tothe methods described in WO91/17991. The following examples serve toillustrate this.

EXAMPLES

1.(−)-cis-8,9-Diethoxy-2-methyl-6-[4-(p-toluenesulfonamido)-phenyl]-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine

A solution of 2.3 g p-toluenesulfonic acid chloride in 5 ml absolutedichloromethane is added dropwise to a solution of 3.5 g(−)-cis-6-(4-Aminophenyl)-8,9-diethoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo-[c][1,6]naphthyridinein 20 ml absolute pyridine, and the mixture is then stirred at roomtemperature for a further 3 h. After the evaporation of the solvents,the residue is extracted with dilute sodium hydroxide solution anddichloromethane. The organic phase is then washed with water, dried oversodium sulfate and concentrated. 5.4 g of the title compound areobtained as rough product, which is recrystallised twice in ethylacetate/methanol. Yield: 4.3 g yellowish crystalls. M.p. 267-268° C.

EF: C₃₀H₃₅N₃O₄S, MW: 533.70

Optical rotation: [α]_(D) ²⁰=−88.4° (c=1, chloroform/methanol, 1+1)[α]_(578 Hg) ²⁰=−93.2° (c=1, chloroform/methanol, 1+1)

2.(−)-cis-9-Ethoxy-8-methoxy-2-methyl-6-[4-(p-toluenesulfonamido)-phenyl]-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine

2.52 g(−)-cis-3-(3-Ethoxy-4-methoxyphenyl)-1-methyl-4-[4-(p-toluenesulfonamido)-benzamido]-piperidineare heated to boiling under reflux for 5 h in 4.3 ml phosphorusoxychloride and 60 ml of acetonitrile. After destilling off the excessacetonitrile and phosphorus oxychloride, the residue is partitionedbetween dichloromethane and saturated sodium hydrogencarbonate solution.The organic phase is washed with water, dried over sodium sulfate andconcentrated. After evaporation of the dichloromethane, the residue ispurified over silica gel by chromatography. The main product fraction isseparated and concentrated. The title compound is obtained afterrecrystallisation in ethyl acetate/diethyl ether (1:10) as faint yellowfine crystalls. M.p. 207-219° C. (unsharp, destruction and redcolouring).

EF: C₂₉H₃₃N₃O₄S×0.88H₂O, MW: 535.49

Optical rotation: [α]_(D) ²⁰=−65.1° (c=1, methanol)

Starting Compounds

A.(−)-cis-3-(3-Ethoxy-4-methoxyphenyl)-1-methyl-4-[4-(p-toluenesulfonamido)-benzamido]-piperidine

The title compound is obtained by reaction of 1.36 g(−)-cis-4-Amino-3-(3-ethoxy-4-methoxyphenyl)-1-methylpiperidine with4-(p-toluenesulfonamido)-benzoyl chloride [prepared from 1.5 g4-(p-toluenesulfonamido)-benzoic acid and thionyl chloride] indichloromethane under addition of triethylamine as auxiliary base. 2.65g are obtained as solid foam. M.p. 100-105° C. (the substance stickstogether from about 93° C.).

EF: C₂₉H₃₅N₃O₅S, MW: 537.68

Optical rotation: [α]_(D) ²⁰=−69.6° (c=1, methanol)

B. (−)-cis4-Amino-3-(3-ethoxy4-methoxyphenyl)-1-methylpiperidinedihydrochloride

The title compound is prepared analogously to the method described in DE4217401, using rac-3-(3-Ethoxy-4-methoxyphenyl)-1-methylpiperid-4-oneinstead of rac-3-(3,4-Dimethoxyphenyl)-1-methylpiperid-4-one as startingmaterial.

EF: C₁₅H₂₄N₂O₂×2HCl×0.96H₂O, MW: 354.52, [colourless crystalls(isopropanol)], m.p. 252-254° C.

Optical rotation: [α]_(D) ²⁰=−65.5° (c=1, methanol)

C. (−)cis-4-Amino-3-(3-ethoxy-4-methoxyphenyl)-1-methylpiperidine

The free base is prepared from the dihydrochloride (compound B) bytreating with dilute sodium hydroxide solution and extraction withdichloromethane. It is used in the next reaction step without furtherpurification.

COMMERCIAL UTILITY

The compounds according to the invention have valuable pharmacologicalproperties which make them commercially utilizable. As potent inhibitorsof type 3, 4 and 5 of cyclic nucleotide phosphodiesterase (PDE3, PDE4and PDE5), they are suitable on the one hand as bronchial therapeutics(for the treatment of airway obstructions on account of their dilatingand cilium-stimulating action but also on account of their respiratoryrate- and respiratory drive-increasing action), but on the other handespecially for the treatment of disorders of inflammatory nature, e.g.of the airways (asthma prophylaxis), of the skin, of the intestine, ofthe eyes and of the joints, which are mediated by mediators such asinterferons, members of the tumor necrosis factor family, interleukins,chemokines, colony-stimulating factors, growth factors, lipid mediators(e.g., inter alia, PAF, platelet-activating factor), bacterial factors(e.g. LPS), immunoglobulins, oxygen free radicals and related freeradicals (e.g. nitrogen monoxide NO), biogenic amines (e.g. histamine,serotonin), kinins (e.g. bradykinin), neurogenic mediators (such assubstance P, neurokinin), proteins such as, for example, granularcontents of leukocytes (inter alia cationic proteins of eosinophils) andadherent proteins (e.g. integrins). The compounds according to theinvention have smooth muscle-relaxant action, e.g. in the region of thebronchial system, of the blood circulation, and of the efferent urinarypassages. Furthermore they have a cilium-frequency increasing action,e.g. in the bronchial system.

In this context, the compounds according to the invention aredistinguished by low toxicity, good human acceptance, great therapeuticbreadth and the absence of significant side effects.

On account of their PDE-inhibiting properties, the compounds accordingto the invention can be employed as therapeutics in human and veterinarymedicine, where they can be used, for example, for the treatment andprophylaxis of the following diseases: acute and chronic (in particularinflammatory and allergen-induced) airway disorders of various origin(bronchitis, allergic bronchitis, bronchial asthma); disorders with areduction of the cilium activity or with increased demands on the ciliarclearance (bronchitis, mucoviscidose); dermatoses (especially ofproliferative, inflammatory and allergic type) such as, for example,psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema,seborrheic eczema, lichen simplex, sunburn, pruritis in the anogenitalarea, alopecia areata, hypertrophic scars, discoid lupus erythematosus,follicular and widespread pyodermias, endogenous and exogenous acne,acne rosacea and other proliferative, inflammatory and allergic skindisorders; disorders which are based on excessive release of TNF andleukotrienes, i.e., for example, disorders of the arthritis type(rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and otherarthritic conditions), systemic lupus erythematosus, disorders of theimmune system (AIDS), including AIDS-related encephalopathies,autoimmune disorders such as diabetes mellitus (Type I, autoimmunediabetes), multiple sclerosis and of the type virus-, bacteria- orparasite-induced demyelinization diseases, cerebral malaria or Lyme'sdisease, shock symptoms [septic shock, endotoxin shock, Gram-negativesepsis, toxic shock syndrome and ARDS (adult respiratory distresssyndrome)] and also generalized inflammations in the gastrointestinalregion (Crohn's disease and ulcerative colitis); disorders which arebased on allergic and/or chronic, faulty immunological reactions in theregion of the upper airways (pharynx, nose) and of the adjacent regions(paranasal sinuses, eyes), such as, for example, allergicrhinitis/sinusitis, chronic rhinitis/sinusitis, allergic conjunctivitisand also nasal polyps; and also disorders of the central nervous systemsuch as memory disorders and Alzheimer's disease, candidiasis,leishmaniases and leprosy.

On account of their vasorelaxant activity, the compounds according tothe invention can also be used for the treatment of high blood pressuredisorders of various origin such as, for example, pulmonary high bloodpressure and the concomitant symptoms associated therewith, for thetreatment of erectile dysfunction or colics of the kidneys and theureters in connection with kidney stones.

On account of their cAMP-increasing action, however, they can also beused for disorders of the heart which can be treated by PDE inhibitors,such as, for example, cardiac insufficiency, and also asanti-thrombotic, platelet aggregation-inhibiting substances.

The invention further relates to a method for the treatment of mammalsincluding humans who are suffering from one of the abovementioneddiseases. The method comprises administering a therapeutically effectiveand pharmacologically tolerable amount of one or more of the compoundsaccording to the invention to the sick mammal.

The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of diseases,especially the diseases mentioned.

The invention also relates to the use of the compounds according to theinvention for the production of medicaments which are employed for thetreatment and/or prophylaxis of the diseases mentioned.

The invention furthermore relates to medicaments for the treatmentand/or prophylaxis of the diseases mentioned and which contain one ormore of the compounds according to the invention.

Advantageously, the substances according to the invention are alsosuitable for combination with other substances which bring aboutstimulation of cAMP, such as prostaglandins (PGE2, PGI2 andprostacyclin) and their derivatives, direct adenylate cyclasestimulators such as forskolin and related substances, or substancesindirectly stimulating adenylate cyclase, such as catecholamines andadrenergic receptor agonists, in particular beta mimetics. Incombination, on account of their cAMP degradation-inhibiting action,they in this case display a synergistic, superadditive activity. Thiscomes to bear, for example, in their use in combination with PGE2 forthe treatment of pulmonary hypertension.

The medicaments are prepared by methods known per se familiar to theperson skilled in the art. As medicaments, the compounds according tothe invention (=active compounds) are either employed as such, orpreferably in combination with suitable pharmaceutical auxiliaries, e.g.in the form of tablets, coated tablets, capsules, suppositories,patches, emulsions, suspensions, gels or solutions, the active compoundcontent advantageously being between 0.1 and 95%.

The person skilled in the art is familiar on the basis of his expertknowledge with the auxiliaries which are suitable for the desiredpharmaceutical formulations. Beside solvents, gel-forming agents,ointments bases and other active compound excipients, it is possible touse, for example, antioxidants, dispersants, emulsifiers, preservatives,solubilizers or permeation promoters.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation. For this purpose, these are administered either directly asa powder (preferably in micronized form) or by atomization of solutionsor suspensions which contain them. With respect to the preparations andadministration forms, reference is made, for example, to the details inEuropean Patent 163 965.

For the treatment of dermatoses, the compounds according to theInvention are used in particular in the form of those medicaments whichare suitable for topical application. For the production of themedicaments, the compounds according to the invention (=activecompounds) are preferably mixed with suitable pharmaceutical auxiliariesand additionally processed to give suitable pharmaceutical formulations.Suitable pharmaceutical formulations which may be mentioned are, forexample, powders, emulsions, suspensions, sprays, oils, ointments, fattyointments, creams, pastes, gels or solutions.

The medicaments according to the invention are prepared by methods knownper se. The dosage of the active compounds takes place in the order ofmagnitude customary for PDE inhibitors. Thus topical application forms(such as, for example, ointments) for the treatment of dermatosescontain the active compounds in a concentration of, for example,0.1-99%. The dose for administration by inhalation is customarilybetween 0.1 and 3 mg per day. The customary dose in the case of systemictherapy (p.o. or i.v.) is between 0.01 and 10 mg/kg per day.

It is of particular interest for the present invention, that thecompounds of formula I according to the invention clearly differ fromthe structurally closest compound of the state of the art—namelytolafentrine—in a surprising and for the person skilled in the art notforeseeable manner (Data are shown below In the chapter “Biologicalinvestigation”).

The in-vitro data presented below for the compounds 1 and 2 (the numberscorrespond to the numbers of the examples) show promise that thecompounds 1 and 2 will have a clearly improved effectiveness in humansin comparison to tolafentrine. The higher potency with regard to thePDE4-inhibition indicates a considerably stronger antiinflammatorycapacity, while the more distinct PDE3/PDE5-inhibition indicates abetter broncholytic effectiveness.

BIOLOGICAL INVESTIGATIONS

In the investigation of PDE4 inhibition at the cellular level, theactivation of inflammatory cells has particular importance. An examplewhich may be mentioned is the FMLP(N-formylmethionylleucylphenylalanine)-induced superoxide production ofneutrophilic granulocytes, which can be measured as luminol-potentiatedchemiluminescence [McPhail L C, Strum S L, Leone P A and Sozzani S, Theneutrophil respiratory burst mechanism. In “Immunology Serie” 1992, 57,47-76; ed. Coffey R G (Marcel Decker, Inc., New York-Basel-Hong Kong)].

Substances which inhibit chemiluminescence, and/or cytokine secretion,and/or the secretion of inflammation-increasing mediators ininflammatory cells, like T-lymphocytes, monocytes, macrophages andgranulocytes are those which inhibit PDE4 or PDE3 and PDE4. The latterisoenzyme of the phosphodiesterase families is particularly representedin granulocytes. Its inhibition leads to an increase in theintracellular cyclic AMP concentration and thus to the inhibition ofcellular activation. PDE4 inhibition by the substances according to theinvention is thus a central indicator of the suppression of inflammatoryprocesses. (Giembycz MA, Could isoenzyme-selective phosphodiesteraseinhibitors render bronchodilatory therapy redundant in the treatment ofbronchial asthma? Biochem Pharmacol 1992, 43, 2041-2051; Torphy T J etal., Phosphodiesterase Inhibitors: new opportunities for treatment ofasthma. Thorax 1991, 46, 512-523; Schudt C et al., Zardaverine: a cyclicAMP PDE3/4 inhibitor. In “New Drugs for Asthma Therapy”, 379-402,Birkhaüser Verlag Basel 1991; Schudt C et al., Influence of selectivephosphodiesterase inhibitors on human neutrophil functions and levels ofcAMP and Ca; Naunyn-Schmiedebergs Arch Pharmacol 1991, 344, 682-690;Tenor H and Schudt C, Analysis of PDE isoenzyme profiles In cells andtissues by pharmacological methods. In “Phosphodiesterase Inhibitors”,21-40, “The Handbook of Immunopharmacology”, Academic Press, 1996;Hatzelmann A et al., Enzymatic and functional aspects of dual-selectivePDE3/4-inhibitors. In “Phosphodiesterase Inhibitors”, 147-160, “TheHandbook of Immunopharmacology”, Academic Press, 1996.

A. Methodology

1. Inhibition of the PDE Isoenzymes

The PDE activity was determined according to Thompson et al. (1) with afew modifications (2). The test samples contained 40 mM tris HCl (pH7.4), 5 mM MgCl₂, 0.5 μM cAMP or cGMP, [³H] cAMP or [³H]cGMP (about50,000 cpm/sample), the PDE isoenzyme-specific additives described ingreater detail below, the given concentrations of inhibitor and analiquot of the enzyme solution in a total sample volume of 200 kd. Stocksolutions of the compounds to be investigated in DMSO were prepared inconcentrations such that the DMSO content in the test samples did notexceed 1% by volume—to avoid affecting the PDE activity. Afterpreincubation at 37° C. for 5 minutes, the reaction was started byaddition of the substrate (cAMP or cGMP). The samples were incubated at37° C. for a further 15 min. The reaction was stopped by addition of 50μl of 0.2N HCl. After cooling on ice for 10 minutes and addition of 25μg of 5′-nucleotidase (snake venom from Crotalus atrox), incubation wascarried out again for 10 min. at 37° C. and the samples were thenapplied to QAE Sephadex A-25 columns. The columns were eluted with 2 mlof 30 mM ammonium formate (pH 6.0). The radioactivity of the eluate wasmeasured and corrected by the corresponding blank values. The proportionof hydrolyzed nucleotide in no case exceeded 20% of the originalsubstrate concentration.

PDE1 (Ca²⁺/calmodulin-dependent) from bovine brain: the inhibition ofthis isoenzyme was investigated in the presence of Ca²⁺ (1 mM) andcalmodulin (100 nM) using cGMP as a substrate (3).

PDE2 (cGMP-stimulated) from rats' hearts was purifiedchromatographically [Schudt et al. (4)] and investigated in the presenceof cGMP (5 μM) using cAMP as a substrate.

PDE3 (cGMP-inhibited) and PDE5 (cGMP-specific) were investigated inhomogenates of human blood platelets [Schudt et al. (4)] using cAMP orcGMP as a substrate.

PDE4 (cAMP-specific) was investigated in the cytosol of humanpolymorphonuclear leucocytes (PMNL) [isolated from leucocyteconcentrates, see Schudt et al. (5)] using cAMP as a substrate. The PDE3inhibitor motapizone (1 μM) was used in order to suppress the PDE3activity emanating from contaminating blood platelets.

2. Inhibition of the Formation of Reactive Oxyyen Species in Human PMNL

The formation of reactive oxygen species determined by means ofluminol-potentiated chemiluminescence (5) and the isolation of the PMNLfrom human blood (6) was carried out essentially as described in (5) and(6): equal-size portions (0.5 ml) of the cell suspension (10⁷ cells/ml)were preincubated at 37° C. for 5 min. In the absence or presence of thecompounds to be investigated in a buffer solution containing 140 mMNaCl, 5 mM KCl, 10 mM HEPES, 1 mM CaCl₂/MgCl₂, 1 mg/ml of glucose, 0.05%(w/v) BSA (bovine serum albumin), 10 μM luminol and 4 μMmicroperoxidase. Stock solutions of the compounds to be investigated inDMSO were prepared in such concentrations that the DMSO content—to avoidan effect on the PDE activity—in the test samples did not exceed 0.1% byvolume. After preincubation, the test samples were additionallytransferred to the measuring apparatus [“Multi-Biolumnat” LB 9505C fromBerthold (Wildbad, Germany)] before stimulation with the receptoragonist FMLP (N-formylmethionylleucylphenylalanine, 100 nM). Thechemiluminescence was recorded continuously for 3 min.; the AUC valueswere calculated from this recording.

3. Statistics

The IC₅₀ values were determined from the concentration inhibition curvesby nonlinear regression using the program GraphPad InPlot™ (GraphPadSoftware Inc., Philadelphia, USA).

4. References

(1) Thompson W. J., Terasaki W. L., Epstein P. M. and Strada S. J.,Assay of cyclic nucleotide phosphodiesterase and resolution of multiplemolecular forms of the enzyme; Adv. Cycl. Nucl. Res. 1979, 10, 69-92

(2) Bauer A. C. and Schwabe U., An improved assay of cyclic3′,5′-nucleotide phosphodiesterase with QAE Sephadex A-25;Naunyn-Schmiedeberg's Arch. Pharmacol. 1980, 311, 193-198

(3) Gietzen K., Sadorf I. and Bader H., A model for the regulation ofthe calmodulin-dependent enzymes erythrocyte Ca²⁺-transport ATPase andbrain phosphodiesterase by activators and inhibitors; Biochem. J. 1982,207, 541-548.

(4) Schudt C., Winder S., Müller B. and Ukena D., Zardaverine as aselective inhibitor of phosphodiesterase isoenzymes; Biochem. Pharmacol.1991, 42, 153-162

(5) Schudt C., Winder S., Forderkunz S., Hatzelmann A. and Ullrich V.,Influence of selective phosphodiesterase inhibitors on human neutrophilfunctions and levels of cAMP and Ca; Naunyn-Schmiedeberg's Arch.Pharmacol. 1991, 344, 682-690

(6) Hatzelmann A. and Ullrich V., Regulation of 5-lipoxygenase activityby the glutathione status in human polymorphonuclearleukocytes; Eur. J.Biochem. 1987, 169, 175-184

B. RESULTS

In Table 1 which follows, the Inhibitory concentrations determinedaccording to Section A1 [inhibitory concentrations as −log IC₅₀ (mol/l)]for the compounds according to the invention are indicated for variousPDE isoenzymes. The numbers of the compounds correspond to the numbersof the examples.

TABLE 1 PDE1 PDE2 PDE3 PDE4 PDE5 Tolafentrine 4.75 6.09 7.02 7.20 5.63 1<5 5.96 7.10 8.60 7.04 2 5.14 6.39 7.28 9.00 6.74

in table 2 below the inhibitory concentrations determined according toSection A2 for tolafentrine and compound 1 are indicated for theFMLP-stimulated chemiluminiscence in human PMNL.

TABLE 2 Inhibition of the FMLP-stimulated chemiluminiscence in humanPMNL in vitro by tolafentnne and compound 1 [inhibitory concentrationsas -log IC₅₀ (mol/l)]. Tolafentrine 6.07 1 7.39

What is claimed is:
 1. A compound of the formula I

in which R1 is ethoxy, R2 is methoxy or ethoxy, or a salt thereof.
 2. Acompound of formula I of claim 1 with the chemical name(−)-cis-8,9-Diethoxy-2-methyl-6-[4-(p-toluenesulfonamido)-phenyl]-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridineor a salt thereof.
 3. A compound of formula I of claim 1 with thechemical name(−)-cis-9-Ethoxy-8-methoxy-2-methyl-6-[4-(p-toluenesulfonamido)-phenyl]-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridineor a salt thereof.
 4. A compound of the formula 1

In which R1 is ethoxy, R2 is methoxy or ethoxy, or a pharmaceuticallyacceptable salt thereof.
 5. A medicament composition comprising aneffective amount of a compound as claimed in claim 4 or apharmaceutically-acceptable salt thereof together with a customarypharmaceutical auxiliary or excipient.
 6. A method of treating a subjectafflicted with an airway disorder, a high blood pressure disorder or aconcomitant disorder connected therewith, which comprises administeringto the subject an effective amount of a compound as claimed in claim 4or of a pharmaceutically-acceptable salt thereof.
 7. A method ofcompounding a medicament composition by combining an active ingredientfor treating an airway disorder with a suitable carrier, wherein theactive ingredient is a compound as claimed in claim 1 or apharmaceutically-acceptable salt thereof.
 8. A method of producing amedicament composition by combining an active ingredient for treating ahigh blood pressure disorder or a concomitant disorder connectedtherewith with a suitable carrier, wherein the active ingredient is acompound as claimed in claim 1 or a pharmaceutically-acceptable saltthereof.
 9. A method for treating a condition amenable to treatment withan active ingredient possessing PDE-inhibiting properties, whichcomprises administering an effective amount of a compound as claimed inclaim 1 or a pharmaceutically-acceptable salt thereof to a subjectafflicted with the condition.